1,5&#39;-Benzodiazepine-2-ones, pharmaceutical compositions thereof and method of use thereof

ABSTRACT

1-Aryl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-ones of the general formula ##STR1## wherein: R 1  is hydrogen, lower alkyl, preferably of 1-3 carbons, or unsaturated lower alkyl preferably of 2-3 carbons 
     R 2 , R 3 , R 4 , R 5  are the same or different and are each hydrogen, halogen, lower alkyl, preferably methyl, lower alkoxy, preferably methoxy, or trifluoromethyl, and 
     R 6 , R 7 , R 8 , R 9  are the same or different and are each hydrogen or lower alkyl, preferably methyl. 
     The compounds are prepared by dehydrohalogenating substituted 2-(3&#39;-halogenopropionylamino)-diphenyl amines of the general formula ##STR2## wherein R 2  to R 9  are the same as defined above and X is halogen, in the presence of a solvent and a base, to cyclize the amines and then alkylating to introduce the unsaturated lower alkyl radical R 1  on the nitrogen in the 5 position, if necessary. The compounds possess anticonvulsant, sedative and muscle relaxant properties.

This application is a divisional of Ser. No. 765,696 now U.S. Pat. No.4,108,852, filed Feb. 4, 1977, which is in turn a continuation of Ser.No. 20,413, filed Mar. 17, 1970 (now abandoned).

This invention relates to1-aryl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-ones and a process ofpreparing the same. The compounds possess valuable pharmacologicalproperties particularly as anticonvulsants, sedatives and musclerelaxants.

The preparation of the compound3,3-diethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one bytreating 1-(o-anilinophenyl)-3,3,-diethyl-azetidin-2-one with diluteacids is disclosed in Helv. Chim. Act. 48:1867, 1965 by B. J. R.Nicolaus et al. See also Chemical Reviews, 68, 747.

The primary object of the invention is the provision of new 1-arylderivatives of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one and a newand improved process of preparing them.

The 1-aryl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-ones compounds ofthe present invention are of the general formula ##STR3## wherein: R₁ ishydrogen, lower alkyl, preferably of 1-3 carbons, or unsaturated loweralkyl, preferably of 2-3 carbons

R₂, R₃, R₄, R₅ are the same or different and are each hydrogen, halogen,preferably chlorine, lower alkyl, preferably methyl, lower alkoxy,preferably methoxy, or trifluoromethyl, and

R₆, R₇, R₈, R₉ are the same or different and are each hydrogen or loweralkyl, preferably methyl.

In general, the process of the present invention comprises cyclizingsubstituted 2-(3'-halogeno-propionylamino)diphenyl amine of the generalformula ##STR4## wherein R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are asdefined above and X is halogen by cleaving hydrogen halide therefrom,preferably in the presence of a solvent and a base, and then introducingthe radical R₁, if it is other than hydrogen, at the nitrogen in the 5position by alkylation.

Since the cyclization reaction occurs by the removal of the hydrogenhalide it is preferred that the reaction be carried out in the presenceof a polar solvent, such as dimethyl formamide, and a base, such as thealkali carbonates or bicarbonates, or sodium amide. It will of course beunderstood that other solvents and bases can be used.

The cyclization reaction can be carried out at temperatures up to about200° C. It can also be carried out at very low temperatures as withsodium amide in liquid ammonia. Compounds in which one or more of thesubstituents R₂, R₃, R₄ or R₅ is halogen can be prepared in anespecially simple manner by simply heating corresponding compounds ofthe general formula II in dimethylformamide to about 100° C. to 150° C.in the presence of potassium carbonate, the reaction being completed inabout 2 hours.

The subsequent alkylation at the nitrogen atom in the 5 position can beaccomplished in a conventional manner. Thus the cyclized compound may bereacted with alkylhalogenides or dialkylsulfates, preferably in thepresence of acid-binding agents, or by reductive alkylation withcarbonyl compounds in the presence of a reducing agent, such ascatalytically energized hydrogen.

It is to be noted that the reaction is surprising since one would expectthe cyclization of substituted2-(3'-halogenopropionylamino)-diphenylamines to produce derivatives of1-aryl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-4-ones, and not compoundsin which the oxygen is in the 2 position, i.e. the 2-one compounds ofthe present invention.

The following are illustrative but non-limitative examples of theinvention.

EXAMPLE 1 1-Phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

A solution of 125 g 2-(3'-chloropropionylamino)diphenylamine in 300 mldimethylformamide is dropped into a boiling suspension of 65 g powderedanhydrous potassium carbonate in 300 ml dimethylformamide under vigorousagitation over a period of about 1/2 hour. Refluxing is continued for 2hours. After cooling, the inorganic salt mixture is removed byfiltration under suction and the solvent is distilled off from thefiltrate under vacuum. The residue is dissolved in 500 ml chloroform,washed twice with water, and the solution is then dried over sodiumsulfate. After distilling off the solvent, the crystalline residue isrecrystallized from 500 ml acetic acid ethyl ester. The yield was 82 gof the compound having an m.p.=170° C.-171° C. (76% of the theory).

The 2-(3'-chloropropionylamino)-diphenylamine (m.p.=115° C.-116° C.,from isopropyl alcohol) used as a starting material is obtained by theinteraction of 2-amino-diphenylamine with 3-chloropropionyl chloride.

EXAMPLE 2

The reaction of Example 1 is carried out using2-(3'-bromopropionylamino)-diphenylamine (m.p.=129° C.-130° C. fromisopropyl alcohol) as the starting material and it can be prepared inthe same manner as 2-(3'chloropropionylamino)diphenylamine.

EXAMPLE 3

8-Chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=179° C.-180° C. (from alcohol) is prepared in the same manner asExample 1.

EXAMPLE 4

1-(4'-Chloro-phenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=233° C.-234° C. (from dimethylformamide) is prepared inthe same manner as Example 1.

EXAMPLE 5

1-(4'-Chloro-phenyl)-8-chloro-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=203° C.-204° C. (from acetic ester) is prepared in thesame manner as Example 1.

EXAMPLE 6

1-(2'-Chloro-phenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=149° C.-150° C. (from acetic ethyl ester) is prepared inthe same manner as Example 1

EXAMPLE 7

1-(3'-Chloro-phenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=183° C.-184° C. (from isopropyl alcohol) is prepared inthe same manner as Example 1.

EXAMPLE 8

1-(2'-Chloro-phenyl)-8-chloro-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=188° C.-189° C. (from isopropyl alcohol) is prepared inthe same manner as Example 1.

EXAMPLE 9

7-Chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=203° C.-204° C. (from ethyl-methyl ketone) is prepared in thesame manner as Example 1.

EXAMPLE 10

9-Chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=213° C.-214° C. (from acetic ethyl ester) is prepared in thesame manner as Example 1.

EXAMPLE 11

9-Chloro-1-(2'-chloro-phenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=212° C.-213° C. (from ethanol) is prepared in the samemanner as Example 1.

EXAMPLE 12 1-Phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

1.2 g sodium is dissolved in 300 ml liquid ammonia and upon the additionof a few granules of iron-(III)-nitrate, i.e. ferric nitrate, it isstirred at about -50° C. for approximately 2 hours until thedisappearance of the blue coloration. 13.7 g of2-(3'-chloropropionylamino)-diphenyl amine is introduced in portionsinto the thus obtained sodium amide suspension. The reaction mixture isstirred still for one 1 hour at about -50° C., the cooling bath isremoved, and the ammonia is allowed to evaporate with stirring. Theresidue is then taken up in chloroform and water, the chloroformsolution is dried over sodium sulfate, and the solvent is distilled off.Upon recrystallization from acetic acid ethyl ester 10.2 g of colorlesscrystals are obtained whose m.p.=170° C.-171° C. (85% of the theory).

EXAMPLE 138-Chloro-5-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

20.4 g 8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-oneis stirred for 2 hours on a water bath with 12.8 g methyl iodide and 10g anhydrous potassium carbonate. The inorganic material is removed byfiltration under suction and the filtrate is diluted with 200 ml water.The crystalline precipitate is filtered under suction, washed withwater, and recrystallized from alcohol. The yield is 20 g of them.p.=143° C.-144° C. (93% of the theory).

EXAMPLE 14

5-Methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=103° C.-104° C. (from diisopropyl ether) is prepared in the samemanner as Example 13.

EXAMPLE 15

5-Ethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one having anm.p.=92° C.-93° C. (from diisopropyl ether) is prepared in the samemanner as Example 13.

EXAMPLE 16

5-Ethyl-8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=132° C.-133° C. (from alcohol) is prepared in the samemanner as Example 13.

EXAMPLE 17

5-Allyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one having anm.p.=71° C.-72° C. (from petroleum ether) is prepared in the same manneras Example 13.

EXAMPLE 185-Allyl-8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=135° C.-136° C. (from alcohol) is prepared in the samemanner as Example 13. EXAMPLE 19

1-(4'-Chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=89° C.-90° C. (from diisopropyl ether) is prepared in thesame manner as Example 13.

EXAMPLE 20

1-(2'-Chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=128° C.-129° C. (from isopropyl alcohol) is prepared inthe same manner as Example 13.

EXAMPLE 21

1-(3'-Chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=87° C.-88° C. (from diisopropyl ether) is prepared in thesame manner as Example 13.

EXAMPLE 22

7-Chloro-5-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=105° C.-106° C. (from diisopropyl ether) is prepared inthe same manner as Example 13.

EXAMPLE 23

8-Chloro-1-(2'-chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=187° C.-188° C. (from isopropyl alcohol) is prepared inthe same manner as Example 13.

EXAMPLE 24

8-Chloro-1-(4'-chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=135° C.-136° C. (from isopropyl alcohol) is prepared inthe same manner as Example 13.

EXAMPLE 25

9-Chloro-5-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=160° C.-161° C. (from isopropyl alcohol) is prepared inthe same manner as Example 13.

EXAMPLE 26

9-Chloro-1-(2'-chloro-phenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=175° C.-176° C. (from isopropyl alcohol) is prepared inthe same manner as Example 13.

EXAMPLE 278-Chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

To a boiling suspension of 37 g powdered anhydrous potassium carbonatein 200 ml dimethylformamide a solution of 97 g2-(3'-bromobutyrylamino)-5-chloro-diphenyl amine in 200 mldimethylformamide is dropped over a period of about 1/2 hour and issubsequently refluxed for 2 hours. Upon cooling, the inorganic saltmixture is removed by filtration under suction and the solvent isdistilled off completely in vacuum from the filtrate. The crystallineresidue is washed with water and recrystallized from isopropanol. Theyield is 59 g having an m.p.=167° C.-168° C. (78% of the theory).

2-(3'-bromobutyrylamino)-5-chloro-diphenylamine (m.p.=171° C.-172° C.,from ethanol) which is used as a starting material is obtained by theinteraction of 2-amino-5-chloro-diphenyl amine with 3-bromo-butyrylchloride.

EXAMPLE 283-Methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

In 250 ml liquid ammonia are dissolved 1.2 g sodium and upon addition ofsome crystals of iron-(III)-nitrate, i.e. ferric nitrate, the mixture isstirred at about -50° C. until disappearance of the blue coloration.Into the suspension of sodium amide formed 17 g2-(3'-bromoisobutyrylamino)-diphenyl amine is introduced in portions.The cooling bath is then removed and the ammonia is evaporated understirring. The crystalline residue is washed with water and isrecrystallized from acetic acid ethyl ester. The yield is 10.5 g havingan m.p.=146° C.-147° C. (83% of the theory).

2-(3'-bromoisobutyrylamino)-diphenyl amine (m.p.=98° C.-99° C. fromisopropyl alcohol) which is used as a starting material is obtained bythe interaction of 2-aminodiphenyl amine with 3-bromo-isobutyrylchloride.

EXAMPLE 29

7-Chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=172° C.-173° C. (from acetic acid ethyl ester) isprepared in the same manner as Examples 27 and 28.

EXAMPLE 30

8-Chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=128° C.-129° C. (from isopropyl alcohol) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 31

4-Methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=130° C.-131° C. (from acetic acid ethyl ester) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 32

7-Chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H,1,5-benzodiazepin-2-one having an m.p.=170° C.-172° C. (from ethanol) isprepared in the same manner as Examples 27 and 28.

EXAMPLE 33

4-Methyl-1-(4'-chlorophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=159° C.-160° C. (from isopropyl alcohol) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 34

3,3-Dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=151° C.-152° C. (from isopropyl alcohol) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 35

8-Chloro-3,3-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=132° C.-133° C. (from isopropyl alcohol) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 36

3,4-Dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=193° C.-194° C. (from ethanol) is prepared in the samemanner as Examples 27 and 28.

EXAMPLE 37

8-Chloro-3,4-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H,1,5-benzodiazepin-2-one having an m.p.=194° C.-195° C. (from ethanol) isprepared in the same manner as Examples 27 and 28.

EXAMPLE 38

4,4-Dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H, 1,5-benzodiazepin-2-onehaving an m.p.=146° C.-147° C. (from diisopropyl ether) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 39

3-Chloro-4,4,-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=180° C.-181° C. (from diisopropyl ether) is prepared inthe same manner as Examples 27 and 28.

EXAMPLE 408-Chloro-4,5-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

28.6 g of8-chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onein 100 ml dimethylformamide is stirred with 18 g methyl iodide and 14 ganhydrous potassium carbonate for 2 hours on a boiling water bath. Thereaction mixture is poured into 500 ml water and extracted with etherseveral times. The ethereal extracts are washed with water and driedover sodium sulfate. Upon distilling off the solvent, the crystallineresidue is recrystallized from acetic acid ethyl ester. The yield is24.5 g having an m.p.=113° C.-114° C. (82% of the theory).

EXAMPLE 41

3,5-Dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=101° C.-102° C. (from diisopropyl-ether) is prepared inthe same manner as Example 40.

EXAMPLE 42

7-Chloro-3,5-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=116° C.-117° C. (from isopropyl alcohol) is prepared inthe same manner as Example 40.

EXAMPLE 43

8-Chloro-3,5-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=151° C. (from isopropyl alcohol) is prepared in the samemanner as Example 40.

EXAMPLE 44

4,5-Dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=97° C.-98° C. (from dimethyl ether) is prepared in thesame manner as Example 40.

EXAMPLE 45

7-Chloro-4,5-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=122° C.-123° C. (from diisopropyl ether) is prepared inthe same manner as Example 40.

EXAMPLE 46

8-Chloro-3,3,5-trimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=191° C.-192° C. (from isopropyl alcohol) is prepared inthe same manner as Example 40.

EXAMPLE 47

8-Chloro-3,4,5-trimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=116° C.-117° C. (from isopropyl alcohol) is prepared inthe same manner as Example 40.

EXAMPLE 48

5-Allyl-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=108° C.-109° C. (from isopropyl alcohol) is prepared inthe same manner as Example 40.

EXAMPLE 49

1-(4'-Chlorophenyl)-4,5-dimethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=80° C.-82° C. (from petroleum ether) is prepared in thesame manner as Example 40.

EXAMPLE 508-Chloro-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

To a boiling suspension of 28 g anhydrous potassium carbonate in 150 mldimethylformamide a solution of 68 g2-(3-chloropropionylamino)-5-chloro-4'-methoxy-diphenyl amine in 150 mldimethylformamide is dropped under stirring over a period of about 1/2hour and, subsequently, the mixture is refluxed for 2 hours. Uponcooling, the inorganic salt mixture is filtered off by suction and thefiltrate is rewashed with dimethylformamide; then the entire solvent isdistilled off under vacuum. The crystalline residue is washed with waterand recrystallized from ethanol. The yield is 44 g having an m.p.=198°C.-199° C. (73% of the theory).

2-(3-chloropropionylamino)-5-chloro-4'-methoxy diphenyl amine m.p.=131°C.-132° C. (from isopropyl alcohol) which is used as a starting materialis obtained by the interaction of 2-amino-5-chloro-4'-methoxy-diphenylamine with 3-chloropropionyl chloride.

EXAMPLE 511-(4'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

In 500 ml liquid ammonia 2,4 g sodium is dissolved and a few granules ofiron-(III)-nitrate, i.e. ferric nitrate, are added. The mixture isstirred at about -50° C. until the disappearance of the blue coloration.29 g 2-(3-chloropropionylamino)-4'-methyl-diphenyl amine is introducedin portions into the suspension of sodium amide so obtained. The coolingbath is then removed and the ammonia is evaporated under stirring. Thecrystalline residue is washed with water and recrystallized fromisopropyl alcohol. The yield is 20.5 g having an m.p.=198° C.-199° C.(81% of the theory).

2-(3-chloropropionylamino)-4'-methyl-diphenyl amine of the m.p.=112°C.-113° C. (from isopropyl alcohol) which is used as a starting materialis obtained by the interaction of 2-amino-4'-methyl-diphenyl amine with3-chloro-propionyl chloride.

EXAMPLE 52

8-Chloro-1-(2'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=150° C.-151° C. (from isopropyl alcohol) is prepared inthe same manner as Example 51.

EXAMPLE 53

1-(2'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=127° C.-128° C. (from acetic acid ethyl ester) isprepared in the same manner as Example 51.

EXAMPLE 54

8-Chloro-1-(2'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=147° C.-148° C. (from acetic acid ethyl ester) isprepared in the same manner as Example 51.

EXAMPLE 55

1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=188° C.-189° C. (from ethanol) is prepared in the samemanner as Example 51.

EXAMPLE 56

8-Chloro-1-(2'-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=168° C.-169° C. (from isopropyl alcohol) is prepared inthe same manner as Example 51.

EXAMPLE 57

1-(3'-Trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=147° C.-148° C. (from diisopropyl ether) is prepared inthe same manner as Example 51.

EXAMPLE 58

3-Methyl-1-(3'-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=168° C.-169° C. (from isopropyl alcohol) is prepared inthe same manner as Example 51.

EXAMPLE 59

8-Chloro-1-(3'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=172° C.-173° C. (from ethanol) is prepared in the samemanner as Example 51.

EXAMPLE 60

8-Chloro-1-(4'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiaxepin-2-onehaving an m.p.=208° C.-209° C. (from ethyl methyl ketone) is prepared inthe same manner as Example 51.

EXAMPLE 61

8-Chloro-1-(3'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=178° C.-179° C. is prepared in the same manner as Example51.

EXAMPLE 62

8-Chloro-1-(4'-bromophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=216° C.-217° C. (from ethyl methyl ketone) is prepared inthe same manner as Example 51.

EXAMPLE 63

8-Chloro-1-(3'-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=148° C.-149° C. (from diisopropyl ether) is prepared inthe same manner as Example 51.

EXAMPLE 64

1-(2',5'-Dichlorophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=197° C.-198° C. (from acetic acid ethyl ester) isprepared in the same manner as Example 51.

EXAMPLE 65

1-(2',6'-Dichlorophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=211°C.-212° C. (from chloroform) is prepared in the samemanner as Example 51.

EXAMPLE 66

7-Methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=164° C.-165° C. (from acetic acid ethyl ester) is prepared inthe same manner as Example 51

EXAMPLE 677-Methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one havingan m.p.=216° C.-217° C. (from glacial acetic acid) is prepared in thesame manner as Example 51. EXAMPLE 68

7,8-Dichloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=193° C.-194° C. (from methanol) is prepared in the samemanner as Example 51.

EXAMPLE 69

1-Phenyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=168° C.-169° C. (from acetic acid ethyl ester/petroleumether) is prepared in the same manner as Example 51.

EXAMPLE 70

1-(2'-Chlorophenyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=176° C.-177° C. (from isopropyl alcohol) is prepared inthe same manner as Example 51.

EXAMPLE 718-Chloro-1-(4'-methoxyphenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

23 g8-chloro-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-oneis stirred in 150 ml dimethylformamide for about 2 hours on a boilingwater bath to which has been added 15 g methyl iodide and 11 g anhydrouspotassium carbonate. The reaction mixture is poured into 1 liter waterwhereby the product is thoroughly crystallized with stirring. Thereaction mixture is filtered by suction, washed thoroughly with water,and crystallized from isopropyl alcohol. The yield is 19 g having anm.p.=144° C.-145° C. (79% of the theory).

EXAMPLE 72

8-Chloro-5-methyl-1-(2'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=148° C.-149° C. (from isopropyl alcohol) is prepared inthe same manner as Example 71.

EXAMPLE 73

1-(2'-Methoxyphenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=129° C.-130° C. (from acetic acid ethyl ester) isprepared in the same manner as Example 71.

EXAMPLE 74

8-Chloro-1-(2'-methoxyphenyl)-5-methyl-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-onehaving an m.p.=150° C.-151° C. (from acetic acid ethyl ester/petroleumether) is prepared in the same manner as Example 71.

EXAMPLE 75

8-Chloro-5-methyl-1-(3'-methylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=135° C.-136° C. (from isopropyl alcohol) is prepared inthe same manner as Example 71.

EXAMPLE 76

8-Chloro-5-methyl-1-(2'-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=116°-117° C. (from 50% ethanol) is prepared in the samemanner as Example 71.

EXAMPLE 77

1-(4'-Methoxyphenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=78° C.-79° C. (from diisopropyl ether) is prepared in thesame manner as Example 71.

EXAMPLE 78

5-Allyl-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an b.p.₀.1 mm =189° C.-192° C. is prepared in the same manner asExample 71.

EXAMPLE 79

5-Methyl-1-(3'-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=104° C.-105° C. (from diisopropyl ether) is prepared inthe same manner as Example 71.

EXAMPLE 80

1-(2',3'-Dichlorophenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=134° C.-135° C. (from isorpopyl alcohol) is prepared inthe same manner as Example 71.

EXAMPLE 81

1-(2',5'-Dichlorophenyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=133° C.-134° C. (from isopropyl alcohol) is prepared inthe same manner as Example 71.

EXAMPLE 82

7,8-Dichloro-5-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-onehaving an m.p.=109° C.-110° C. (from isopropyl alcohol) is prepared inthe same manner as Example 71.

EXAMPLE 83 1-Phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

9.2 g of 2-amino-diphenylamine and 4.5 g acrylic acid in 20 ml of 5 Nsulfuric acid are heated under reflux for 3 hours. After completion ofthe reaction, the reaction mixture is made alkaline by the addition ofconcentrated aqueous ammonia solution. The oily reaction product isextracted with chloroform and the chloroform solution is washed withwater, dried over sodium sulfate and the solution is distilled off. Theresidue is recrystallized from isopropyl alcohol. The yield is 1.2 ghaving an m.p.=169° C.-170° C. (10% of the theory).

It should be noted further that the compounds of the invention whereinR₂, R₃, R₄ and R₅ are halogen are preferably prepared at lowtemperatures as, for example, with sodium amide in liquid ammonia.

The compounds of the invention are preferably administered orally in theform of tablets, capsules and dragees but can be administered in othersuitable forms. They are preferably diluted with suitable dilutingagents, thus, allowing better and more economical use to be madethereof.

As solid carriers, which are suitable for the manufacture of usefulpharmaceutical preparations, various inert pulverulent distributingagents as they are conventionally used in pharmaceutical compounding maybe employed.

When preparing tablets, capsules, dragees and the like, the commonlyused diluting agents, binders, lubricants, and the like are added, suchas sugar, lactose, talcum, starch, pectins; as binders gelatin, gumarabic, methyl cellulose, yeast extract, agar, tragacanth, and aslubricating agents, magnesium stearate, stearic acid, and others.

The compounds of the invention are useful for the treatment of anxiety,for skeletal muscle relaxation and for combating alcoholism. A dailytherapeutic dosage can be maintained by administering 10 to 100 mg ofthe compound in suitable dosage units as, for example, 2, 5, 10, 25 and50 mg per tablet, capsule or dragee. The daily dosage must be adjustedto the individual needs for the patient. For ordinary anxiety a dailydosage of 10-30 mg is preferred while 100 mg per day may be required formore severely disturbed patients.

The activities of the new compounds were determined in the followingtests:

(1) The acute toxity was determined according to J. F. Litchfield, F.Wilcoxon, J. Pharmacol. and Exp. Therap. 96, 99-113 (1949).

(2) The sedative activity was determined according to J. Stewart, Am. J.Physiol. 1, 40 (1898).

(3) The anticonvulsant activity was determined according to the methodsintroduced by C. S. Goodman et al. Arch. int. Pharmacodyn 78, 144-162(1949) and by C. S. Goodman et al. J. Pharm. exp. Ther. 108, 168-176(1953).

In all tests the new compounds showed much better results thanmeprobamat.

What is claimed is:
 1. A1-aryl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one of the formula##STR5## wherein R₁ is hydrogen, lower alkyl, or unsaturated loweraliphatic hydrocarbon; R₄ and R₅ are the same or different and each ishydrogen, halogen, lower alkyl, lower alkoxy, or trifluoromethyl, but ifone of R₄ and R₅ is halogen or trifluoromethyl and the other of R₄ andR₅ is hydrogen, then the halogen or trifluoromethyl substituent is inthe para-position; and R₆, R₇, R₈, and R₉ are the same or different andeach is hydrogen or lower alkyl.
 2. A compound as in claim 1 wherein R₁is hydrogen, lower alkyl having 1 to 3 carbon atoms, or unsaturatedaliphatic hydrocarbon having 2 to 3 carbon atoms and R₆, R₇, R₈, and R₉are the same or different and each is hydrogen or methyl.
 3. A compoundas in claim 1 wherein R₁ is hydrogen, methyl, ethyl, or allyl; R₄ ishydrogen, fluoro, chloro, bromo, methyl, methoxy, or trifluoromethyl; R₅is hydrogen or chloro; and R₆, R₇, R₈, and R₉ are the same or differentand each is hydrogen or methyl but at least two of R₆ -R₉ are hydrogen.4. A compound as in claim 2 wherein R₄ and R₅ are both hydrogen.
 5. Acompound as in claim 2 wherein R₄ is hydrogen and R₅ is chlorine.
 6. Acompound as in claim 2 wherein R₄ and R₅ are both methyl.
 7. A compoundas in claim 2 wherein R₄ is hydrogen and R₅ is methoxy.
 8. A compound asin claim 1 which has the formula ##STR6##
 9. A compound as in claim 1which is8-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.
 10. Acompound as in claim 1 which is8-chloro-5-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.11. A compound as in claim 1 which is8-chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.12. A compound as in claim 1 which is8-chloro-4,5-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.13. A compound as in claim 1 which is8-chloro-1-(4'-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one.14. A sedative composition comprising an effective sedative amount of acompound as in claim 1 and an inert pharmaceutical carrier, in dosageunit form.
 15. A sedative composition comprising an effective sedativeamount of a compound as in claim 2 and an inert pharmaceutical carrier,in dosage unit form.
 16. The method of producing a sedative sedativeeffect in a patient which comprises orally administering to said patientan effective amount of a compound as in claim
 1. 17. The method ofproducing a sedative sedative effective in a patient which comprisesorally administering to said patient an effective amount of a compoundas in claim 2.